Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

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    Fermentation of Chicory Fructo-Oligosaccharides and Native Inulin by Infant Fecal Microbiota Attenuates Pro-Inflammatory Responses in Immature Dendritic Cells in an Infant-Age-Dependent and Fructan-Specific Way
    Logtenberg, Madelon J. ; Akkerman, Renate ; An, Ran ; Hermes, Gerben D.A. ; Haan, Bart J. de; Faas, Marijke M. ; Zoetendal, Erwin G. ; Schols, Henk A. ; Vos, Paul de - \ 2020
    Molecular Nutrition & Food Research 64 (2020)13. - ISSN 1613-4125
    dendritic cells - in vitro fermentation - infant formula - inulin-type fructans - microbiota

    Scope: Inulin-type fructans are commonly applied in infant formula to support development of gut microbiota and immunity. These inulin-type fructans are considered to be fermented by gut microbiota, but it is unknown how fermentation impacts immune modulating capacity and whether the process of fermentation is dependent on the infant's age. Methods and results: The in vitro fermentation of chicory fructo-oligosaccharides (FOS) and native inulin are investigated using pooled fecal inocula of two- and eight-week-old infants. Both inocula primarily utilize the trisaccharides in FOS, while they almost completely utilize native inulin with degree of polymerization (DP) 3–8. Fecal microbiota of eight-week-old infants degrades longer chains of native inulin up to DP 16. This correlates with a higher abundance of Bifidobacterium and higher production of acetate and lactate after 26 h of fermentation. Fermented FOS and native inulin attenuate pro-inflammatory cytokines produced by immature dendritic cells (DCs), but profiles and magnitude of attenuation are stronger with native inulin than with FOS. Conclusion: The findings demonstrate that fermentation of FOS and native inulin is dependent on the infant's age and fructan structure. Fermentation enhances attenuating effects of pro-inflammatory responses in DCs, which depend mainly on microbial metabolites formed during fermentation.

    Higher Chain Length Distribution in Debranched Type-3 Resistant Starches (RS3) Increases TLR Signaling and Supports Dendritic Cell Cytokine Production
    Lépine, Alexia F.P. ; Hilster, Roderick H.J. de; Leemhuis, Hans ; Oudhuis, Lizette ; Buwalda, Piet L. ; Vos, Paul de - \ 2019
    Molecular Nutrition & Food Research 63 (2019)2. - ISSN 1613-4125
    Caco-2 - dendritic cells - resistant starches - T-cells - Toll-like receptors

    Scope: Resistant starches (RSs) are classically considered to elicit health benefits through fermentation. However, it is recently shown that RSs can also support health by direct immune interactions. Therefore, it has been hypothesized that the structural traits of RSs might impact the health benefits associated with their consumption. Methods and results: Effects of crystallinity, molecular weight, and chain length distribution of RSs are determined on immune Toll-like receptors (TLRs), dendritic cells (DCs), and T-cell cytokines production. To this end, four type-3 RSs (RS3) are compared, namely Paselli WFR, JD150, debranched Etenia, and Amylose fraction V, which are extracted from potatoes and enzymatically modified. Dextrose equivalent seems to be the most important feature influencing immune signaling via activation of TLRs. TLR2 and TLR4 are most strongly stimulated. Especially Paselli WFR is a potent activator of multiple receptors. Moreover, the presence of amylose, even to residual levels, enhances DC and T-cell cytokine responses. Paselli WFR and Amylose fraction V influence T-cell polarization. Conclusions: It has been shown here that chain length and particularly dextrose equivalent are critical features for immune activation. This knowledge might lead to tailoring and design of immune-active RS formulations.

    Synbiotic Effects of the Dietary Fiber Long-Chain Inulin and Probiotic Lactobacillus acidophilus W37 Can be Caused by Direct, Synergistic Stimulation of Immune Toll-Like Receptors and Dendritic Cells
    Lépine, Alexia ; Vos, Paul de - \ 2018
    Molecular Nutrition & Food Research 62 (2018)15. - ISSN 1613-4125
    Caco-2 - dendritic cells - inulin-type fructans - Lactobacillus acidophilus W37 - Salmonella Typhimurium

    Scope: Synbiotic effects of dietary fibers and lactobacilli are usually explained by synergistic modulation of gut microbiota. New insight, however, has demonstrated that both dietary fibers and lactobacilli can directly stimulate immune cells and benefit consumer immunity. Here, the synergistic effects of immune active long-chain inulin (lcITF) and Lactobacillus acidophilus W37 (LaW37) on dendritic cells (DCs) are investigated. Methods and results: Effects of lcITF and LaW37 alone or combined were studied on Toll-like receptor (TLRs) signaling and cytokine secretion by DCs in the presence and absence of media of intestinal epithelial cell (IEC) exposed to the ingredients. Also, the effects of DC responses against Salmonella Typhimurium (STM) were investigated. Synergistic effects were observed on TLR2 and 3. Synergistic effects were not always pro-inflammatory. LaW37 was strongly pro-inflammatory, while cytokine responses were regulatory when combined with lcITF. Exposure of DCs to IECs medium changed the DCs’ response, which revealed synergistic enhancing effects of lcITF/LaW37 on production of IL-6 and IL-8. DCs’ response in the presence of STM and LaW37 were so strong that lcITF had no additional effect. Conclusion: It is demonstrated that synbiotic effects of dietary fibers and bacteria are not limited to the effects on gut microbiota but can also occur by synergistically directly stimulating IECs and/or immune cells.

    Biomarkers and mechanisms of natural disease resistance in dairy cows
    Altena, S.E.C. van - \ 2016
    Wageningen University. Promotor(en): Huub Savelkoul, co-promotor(en): Edwin Tijhaar. - Wageningen : Wageningen University - ISBN 9789462578005 - 158
    dairy cows - biomarkers - disease resistance - immunity - antibodies - proteomics - immune response - dendritic cells - immunology - melkkoeien - biomarkers - ziekteresistentie - immuniteit - antilichamen - eiwitexpressieanalyse - immuniteitsreactie - dendritische cellen - immunologie

    The aim of this thesis was to define and test biomarkers for disease resistance in dairy cows and to determine the underlying mechanism in natural disease resistance. The health status of the cows is an important issue in dairy farming. Due to the mandatory reduction in the use of antibiotics, alternatives are required to prevent the development and expression of illness in dairy cows. The identification of biomarkers associated with such disease offers the opportunity to adapt the management of cows at risk, and in this way, prevent them from developing overt disease. Previously, natural antibodies (NAbs) in serum and milk were used as candidate biomarkers for natural disease resistance in cows. In this thesis, we continue on the occurrence and mode of action of NAbs and also focus on their source: the B-1 cells. We performed a literature study on the identification and function of B-1 cells in different species and defined the limitations in the current identification of these cells in pigs, sheep and cows (Chapter 2). B-1 cells were described in cows by using widely accepted cell surface markers CD5 and CD11b. However, in literature several findings suggest that these cell surface markers are not unique markers for B-1 identification. The similarities between mice and veterinary animals in foetal B-cell development and antibody production, implies that B-1 cells are present in cows. In chapter 3, we carefully studied new markers to selectively identify B-1 cells in cows. The combination of B-1 cell markers IgM++ and pSYK++ (indicator constitutive intracellular signalling) identifies a distinct cell population with essential B-1 characteristics such as high CD80 expression. In addition, the development of these B-1 cells in calves before colostrum intake and 3 weeks afterwards shows the same kinetics as the development of NAbs represented by IgM antibodies binding to the well-accepted NAb-antigen phosphatidylcholine (PtC). In calves up to half a year of age, it is shown that the production of such NAbs increases from birth and stabilises from 6 weeks onwards. This implies an endogenous NAb production, which follows the same age-related kinetics as can be expected from B-1 cell development. In contrast, the development of total IgM antibody levels in calves shows a bimodal distribution, which is caused by the uptake and breakdown of maternally-derived IgM and simultaneous endogenous production of specific and natural IgM. Chapter 4 describes the role of such NAbs in bovine immunity. NAbs were represented by the binding of IgM to the naïve antigen keyhole limpet hemocyanin (KLH). Cows with high serum NAb levels were shown to have more IgM and IgG antibodies binding to common microbial structures LPS, LTA and PGN, than cows with low serum NAb levels. In addition, they also have more IgM antibodies binding to intact, fixed E. coli and S. Typhimurium bacteria. However, the killing of live E. coli and S. Typhimurium bacteria via antibody-mediated complement killing does not differ between cows with high and low NAb levels. The antibody-mediated complement killing was determined in a newly developed serum bactericidal test. Cows that performed less in the bactericidal test were more likely to develop mastitis in the future. This association was observed for the killing of E. coli and S. Typhimurium and the development of mastitis within the next one year. For S. Typhimurium the association was still present for the cases of mastitis occurring within four years after testing. Alternative biomarkers for disease resistance in cows were defined in chapter 5 by using a contemporary proteomics approach. Milk samples from high and low disease resistant cows were selected from the “Resilient Cattle” (Weerbaar Vee) biobank. Comparing the spectrum of milk proteins of high and low disease-resistant cows showed potential candidate biomarkers that were elevated in the milk of low-resistant cows. Two candidate marker proteins were validated with ELISA in a new and larger group of high- and low-resistant cows. Lactoferrin (LF) levels were significantly increased in milk of low-resistant cows. In addition, LF levels in milk were associated with clinical manifestations of lameness and had a predictive value for subsequent culling.

    In conclusion, we found that also in cows NAbs are produced by B-1 cells that can be identified based on the combined expression of cell surface IgM and internal pSYK. In addition, the frequency of these B-1 cells after birth follows a similar kinetics as described before in mice. These NAbs can be more precisely identified based on their PtC binding ability and their functional activity in a bactericidal test. However, the true predictive value of B-1 cells and NAbs for the health status and immunocompetence of dairy cattle remains to be established. Proteomics turned out to be a useful approach for identifying potential new biomarkers for health and disease in milk of cows. Application and further development of their predictive capacity is dependent on the availability of robust, sensitive and quantitative assays. This project was part of the “Resilient Cattle” project providing biological samples and essential data on the health status during respective lactation periods of individual dairy cows. The impact of this research now requires translation into management tools and principles for the individual farmer impacting on the overall health status and economic performance of his herd of dairy cattle.

    Toll-Like Receptor 2 Activation by beta 2 -> 1-Fructans Protects Barrier Function of T84 Human Intestinal Epithelial Cells in a Chain Length-Dependent Manner
    Vogt, L.M. ; Meyer, D. ; Pullens, G. ; Faas, M.M. ; Venema, K. ; Ramasamy, U. ; Schols, H.A. ; Vos, P. - \ 2014
    The Journal of Nutrition 144 (2014)7. - ISSN 0022-3166 - p. 1002 - 1008.
    cerebral ischemia/reperfusion injury - kinase-c isoforms - dietary fiber - bronchial-asthma - tyrosine kinase - dendritic cells - gut microbiota - celiac-disease - fatty-acids - pkc-alpha
    Dietary fiber intake is associated with lower incidence and mortality from disease, but the underlying mechanisms of these protective effects are unclear. We hypothesized that beta 2 -> 1-fructan dietary fibers confer protection on intestinal epithelial cell barrier function via Toll-like receptor 2 (TLR2), and we studied whether beta 2 -> 1-fructan chain-length differences affect this process. T84 human intestinal epithelial cell monolayers were incubated with 4 beta 2 -> 1-fructan formulations of different chain-length compositions and were stimulated with the proinflammatory phorbol 12-myristate 13-acetate (PMA). Transepithelial electrical resistance (TEER) was analyzed by electric cell substrate impedance sensing (ECIS) as a measure for tight junction-mediated barrier function. To confirm TLR2 involvement in barrier modulation by beta 2 -> 1-fructans, ECIS experiments were repeated using TLR2 blocking antibody. After preincubation of T84 cells with short-chain beta 2 -> 1-fructans, the decrease in TEER as induced by PMA (62.3 +/- 5.2%, P <0.001) was strongly attenuated (15.2 8.8%, P <0.01). However, when PMA was applied first, no effect on recovery was observed during addition of the fructans. By blocking TLR2 on the T84 cells, the protective effect of short-chain beta 2 -> 1-fructans was substantially inhibited. Stimulation of human embryonic kidney human TLR2 reporter cells with beta 2 -> 1-fructans induced activation of nuclear factor kappa-light-chain-enhancer of activated B cells, confirming that beta 2 -> 1-fructans are specific ligands for TLR2. To conclude, beta 2 -> 1-fructans exert time-dependent and chain length-dependent protective effects on the T84 intestinal epithelial cell barrier mediated via TLR2. These results suggest that TLR2 located on intestinal epithelial cells could be a target of beta 2 -> 1-fructan-mediated health effects.
    Mannose-Binding Lectin Is Required for the Effective Clearance of Apoptotic Cells by Adipose Tissue Macrophages During Obesity
    Stienstra, R. ; Dijk, W. ; Beek, L. van; Jansen, H. ; Heemskerk, M. ; Houtkooper, R.H. ; Denis, S. ; Harmelen, V. van; Willems van Dijk, K. ; Tack, C.J. ; Kersten, A.H. - \ 2014
    Diabetes 63 (2014)12. - ISSN 0012-1797 - p. 4143 - 4153.
    insulin-resistance - cytokine secretion - hepatic steatosis - dendritic cells - deficient mice - tnf-alpha - innate - protein - inflammation - adipocytes
    Obesity is accompanied by the presence of chronic low-grade inflammation manifested by infiltration of macrophages into adipose tissue. Mannose-binding lectin (MBL), a soluble mediator of innate immunity, promotes phagocytosis and alters macrophage function. To assess the function of MBL in the development of obesity, we studied wild-type and MBL-/- mice rendered obese using a high-fat diet (HFD). Whereas no gross morphological differences were observed in liver, an HFD provoked distinct changes in the adipose tissue morphology of MBL-/- mice. In parallel with increased adipocyte size, MBL-/- mice displayed an increased influx of macrophages into adipose tissue. Macrophages were polarized toward an alternatively activated phenotype known to modulate apoptotic cell clearance. MBL deficiency also significantly increased the number of apoptotic cells in adipose tissue. Consistent with these observations, recombinant MBL enhanced phagocytic capacity of the stromal vascular fraction isolated from adipose tissue and modulated uptake of apoptotic adipocytes by macrophages. Despite changes in macrophage abundance and polarity, the absence of MBL did not affect systemic insulin resistance. Finally, in humans, lower levels of circulating MBL were accompanied by enhanced macrophage influx in subcutaneous adipose tissue. We propose a novel role for MBL in the recognition and clearance of apoptotic adipocytes during obesity.
    Protein transport across the small intestine in food hypersensitivity
    Reitsma, M. ; Westerhout, J. ; Wichers, H.J. ; Wortelboer, H. ; Verhoeckx, K.C.M. - \ 2014
    Molecular Nutrition & Food Research 58 (2014)1. - ISSN 1613-4125 - p. 194 - 205.
    transepithelial antigen transport - undegraded dietary antigen - simulated gastric fluid - human peyers-patches - dendritic cells - macromolecular transport - in-vitro - beta-lactoglobulin - immune-system - epithelial exosomes
    In view of the imminent deficiency of protein sources for human consumption in the near future, new protein sources need to be identified. However, safety issues such as the risk of allergenicity are often a bottleneck, due to the absence of predictive, validated and accepted methods for risk assessment. The current strategy to assess the allergenic potential of proteins focuses mainly on homology, stability and cross-reactivity, although other factors such as intestinal transport might be of added value too. In this review, we present an overview of the knowledge of protein transport across the intestinal wall and the methods currently being used to measure this. A literature study reveals that protein transport in sensitised persons occurs para-cellularly with the involvement of mast cells, and trans-cellularly via enterocytes, while in non-sensitised persons micro-fold cells and enterocytes are considered most important. However, there is a lack of comparable systematic studies on transport of allergenic proteins. Knowledge of the multiple protein transport pathways and which model system can be useful to study these processes may be of added value in the risk assessment of food allergenicity.
    Human milk: a source of more life than we imagine
    Jeurink, P.V. ; Bergenhenegouwen, J. van; Jimenez, E. ; Knippels, L.M.J. ; Fernandez, L. ; Garssen, J. ; Knol, J. ; Rodriguez, J.M. ; Martin, R. - \ 2013
    Beneficial Microbes 4 (2013)1. - ISSN 1876-2883 - p. 17 - 30.
    lactic-acid bacteria - human breast-milk - fragment-length-polymorphism - human skin microbiome - healthy women - infectious mastitis - dendritic cells - infant gut - staphylococcus-epidermidis - intestinal microbiota
    The presence of bacteria in human milk has been acknowledged since the seventies. For a long time, microbiological analysis of human milk was only performed in case of infections and therefore the presence of non-pathogenic bacteria was yet unknown. During the last decades, the use of more sophisticated culture-dependent and -independent techniques, and the steady development of the -omic approaches are opening up the new concept of the 'milk microbiome', a complex ecosystem with a greater diversity than previously anticipated. In this review, possible mechanisms by which bacteria can reach the mammary gland (contamination versus active migration) are discussed. In addition, the potential roles of human milk for both infant and maternal health are summarised. A better understanding of the link between the milk microbiome and health benefit, the potential factors influencing this relationship and whether or not it can be influenced by nutrition is required to open new avenues in the field of pregnancy and lactation.
    Immune Modulation by Different Types of ß2¿1-Fructans Is Toll-Like Receptor Dependent
    Vogt, L. ; Ramasamy, U. ; Meyer, D. ; Pullens, G. ; Venema, K. ; Faas, M.M. ; Schols, H.A. ; Vos, P. de - \ 2013
    PLoS ONE 8 (2013)7. - ISSN 1932-6203 - 12 p.
    chain fatty-acids - nf-kappa-b - blood mononuclear-cells - dendritic cells - lactobacillus-rhamnosus - bifidobacterium-lactis - signal-transduction - innate immunity - dietary fiber - inulin
    Introduction ß2¿1-fructans are dietary fibers. Main objectives of this study were 1) to demonstrate direct signalling of ß2¿1-fructans on immune cells, 2) to study whether this is mediated by the pattern recognition receptors Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain-containing proteins (NODs), and 3) to relate the observed effects to the chain length differences in ß2¿1-fructans. Methods Four different ß2¿1-fructan formulations were characterised for their chain length profile. Human peripheral blood mononuclear cells (PBMCs) were stimulated in vitro with ß2¿1-fructans, and production of IL-1Ra, IL-1ß, IL-6, IL-10, IL-12p70, and TNF-a was analysed. Reporter cells for TLRs and NODs were incubated with ß2¿1-fructans and analysed for NF-¿B/AP-1 activation. Results Cytokine production in human PBMCs was dose- and chain length-dependent. Strikingly, short chain enriched ß2¿1-fructans induced a regulatory cytokine balance compared to long chain enriched ß2¿1-fructans as measured by IL-10/IL-12 ratios. Activation of reporter cells showed that signalling was highly dependent on TLRs and their adapter, myeloid differentiation primary response protein 88 (MyD88). In human embryonic kidney reporter cells, TLR2 was prominently activated, while TLR4, 5, 7, 8, and NOD2 were mildly activated. Conclusions ß2¿1-fructans possess direct signalling capacity on human immune cells. By activating primarily TLR2, and to a lesser extent TLR4, 5, 7, 8, and NOD2, ß2¿1-fructan stimulation results in NF-¿B/AP-1 activation. Chain length of ß2¿1-fructans is important for the induced activation pattern and IL-10/IL-12 ratios.
    Phenotypic modulation and cytokine profiles of antigen presenting cells by European subtype 1 and 3 porcine reproductive and respiratory syndrome virus strains in vitro and in vivo
    Weesendorp, E. ; Stockhofe-Zurwieden, N. ; Popma-de Graaf, D.J. ; Fijten, H.P.D. ; Rebel, J.M.J. - \ 2013
    Veterinary Microbiology 167 (2013)3-4. - ISSN 0378-1135 - p. 638 - 650.
    dendritic cells - immune-responses - pigs - prrsv - infection - apoptosis - genotype - disease - lungs - interleukin-10
    Porcine reproductive and respiratory syndrome virus (PRRSV) causes continuous problems in the pig industry, due to high costs of outbreaks and reduced welfare of diseased pigs. The severity of infection is, partly, dependent on the virus strain. Recently isolated Eastern-European subtype 3 strains are more pathogenic than the widespread subtype 1 strains. There is, however, almost no information available about the mechanisms involved in the pathogenicity of these subtype 3 strains. The objective of the present study was to characterize the in vitro and in vivo response of two European subtype 1 strains, Belgium A and Lelystad-Ter Huurne (LV), and a virulent subtype 3 strain, Lena, in bone marrow-derived dendritic cells (BM-DC) (in vitro) and alveolar macrophages (in vitro and in vivo). It was shown that infection with the Lena strain resulted in a higher apoptosis of cells in vitro and a higher level of infectivity in vitro and in vivo than the other virus strains. Furthermore, infection with Lena resulted in a small downregulation of the immunologically relevant cell surface molecules SLA-I, SLA-II and CD80/86 in vitro, and SLA-II in vivo. In spite of these differences, in vitro cytokine responses did not differ significantly between strains, except for the absence of IL-10 production by Lena in BM-DC. The higher infectivity, apoptosis and downregulation of the cell surface molecules, may have contributed to the increased pathogenicity of Lena, and have dampened specific immune responses. This could explain the delayed and decreased adaptive immune responses observed after infections with this strain.
    The Impact of Lactobacillus plantarum WCFS1 Teichoic Acid D-Alanylation on the Generation of Effector and Regulatory T-cells in Healthy Mice
    Smelt, M.J. ; Haan, B.J. de; Bron, P.A. ; Swam, I. van; Meijerink, M. ; Wells, J. ; Kleerebezem, M. ; Faas, M.M. ; Vos, P. de - \ 2013
    PLoS ONE 8 (2013)4. - ISSN 1932-6203 - 14 p.
    placebo-controlled trial - inflammatory-bowel-disease - blood mononuclear-cells - tlr signaling pathways - lipoteichoic acid - double-blind - dendritic cells - ulcerative-colitis - maintaining remission - acidophilus deficient
    To date it remains unclear how probiotics affect the immune system. Bacterial envelope components may play an essential role, as these are the first to establish bacterial-host cell interactions. Teichoic acids (TAs), and especially lipoteichoic acids, are the most pro-inflammatory components of the gram-positive bacterial envelope. This effect is dependent on D-alanyl substitution of the TA backbone and interactions with TLR2 on host cells. Although the pro-inflammatory properties of TAs have been established in vitro, it remains unclear how TAs affect immunomodulation in vivo. In this study, we investigated the role of TA D-alanylation on L. plantarum–induced intestinal and systemic immunomodulation in vivo. For this, we compared the effect of L. plantarum WCFS1 and its TA D-Alanylation negative derivative (dltX-D) on the distribution of dendritic cell and T cell populations and responses in healthy mice. We demonstrated that the majority of the L. plantaruminduced in vivo immunomodulatory effects were dependent on D-alanylation (D-Ala), as some L. plantarum WCFS1-induced immune changes were not observed in the dltX-D-treated group and some were only observed after treatment with dltX-D. Strikingly, not only pro-inflammatory immune responses were abolished in the absence of D-Ala substitution, but also antiinflammatory responses, such as the L. plantarum-induced generation of regulatory T cells in the spleen. With this study we provide insight in host-microbe interactions, by demonstrating the involvement of D-alanylation of TAs on the bacterial membrane in intestinal and systemic immunomodulation in healthy mice.
    Using recombinant Lactococci as an approach to dissect the immunomodulating capacity of surface piliation in probiotic Lactobacillus rhamnosus GG
    Ossowski, I. von; Pietilä, T.E. ; Rintahaka, J. ; Nummenmaa, E. ; Mäkinen, V.M. ; Reunanen, J. ; Satokari, R.M. ; Vos, W.M. de; Palva, I. ; Palva, A. - \ 2013
    PLoS ONE 8 (2013)5. - ISSN 1932-6203
    lactic-acid bacteria - intestinal epithelial-cells - functional-analysis - dendritic cells - gastrointestinal-tract - dependent mechanism - protein-production - oral consumption - adhesion - pili
    Primarily arising from their well understood beneficial health effects, many lactobacilli strains are considered good candidates for use as probiotics in humans and animals. Lactobacillar probiosis can itself be best typified by the Lactobacillus rhamnosus GG strain, which, with its well-documented clinical benefits, has emerged as one of the most widely used probiotics in the food and health-supplement industries. Even so, many facets of its molecular mechanisms and limitations as a beneficial commensal bacterium still remain to be thoroughly explored and dissected. Because L. rhamnosus GG is one of only a few such strains exhibiting surface piliation (called SpaCBA), we sought to examine whether this particular type of cell-surface appendage has a discernible immunomodulating capacity and is able to trigger targeted responses in human immune-related cells. Thus, presented herein for this study, we recombinantly engineered Lactococcus lactis to produce native (and pilin-deleted) SpaCBA pili that were assembled in a structurally authentic form and anchored to the cell surface, and which had retained mucus-binding functionality. By using these recombinant lactococcal constructs, we were able to demonstrate that the SpaCBA pilus can be a contributory factor in the activation of Toll-like receptor 2-dependent signaling in HEK cells as well as in the modulation of pro- and anti-inflammatory cytokine (TNF-a, IL-6, IL-10, and IL-12) production in human monocyte-derived dendritic cells. From these data, we suggest that the recombinant-expressed and surface-anchored SpaCBA pilus, given its projected functioning in the gut environment, might be viewed as a new microbe-associated molecular pattern (MAMP)-like modulator of innate immunity. Accordingly, our study has brought some new insight to the molecular immunogenicity of the SpaCBA pilus, thus opening the way to a better understanding of its possible role in the multifaceted nature of L. rhamnosus GG probiosis within the human gut
    Pathway analysis in blood cells of pigs infected with classical swine fever virus: comparison of pigs that develop a chronic form of infection or recover
    Hulst, M.M. ; Loeffen, W.L.A. ; Weesendorp, E. - \ 2013
    Archives of Virology 158 (2013)2. - ISSN 0304-8608 - p. 325 - 339.
    viral-diarrhea-virus - interferon regulatory factor-3 - double-stranded-rna - c-reactive protein - n-pro product - systemic-lupus-erythematosus - kappa-b-alpha - dendritic cells - indoleamine 2,3-dioxygenase - proteasomal degradation
    Infection of pigs with CSFV can lead to either acute disease, resulting in death or recovery, or chronic disease. The mechanisms by which CSFV manipulates the pig’s first line of defence to establish a chronic infection are poorly understood. Therefore, pigs were infected with moderately virulent CSFV, and whole blood was collected on a regular basis during a period of 18 days. Using whole-genome microarrays, time-dependent changes in gene expression were recorded in blood cells of chronically diseased pigs and pigs that recovered. Bioinformatics analysis of regulated genes indicated that different immunological pathways were regulated in chronically diseased pigs compared to recovered pigs. In recovered pigs, antiviral defence mechanisms were rapidly activated, whereas in chronically diseased pigs, several genes with the potential to inhibit NF-¿B- and IRF3/7-mediated transcription of type I interferons were up-regulated. Compared to recovered pigs, chronically diseased pigs failed to activate NK or cytotoxic T-cell pathways, and they showed decreased gene activity in antigen-presenting monocytes/macrophages. Remarkably, in chronically diseased pigs, genes related to the human autoimmune disease systemic lupus erythematosus (SLE) were up-regulated during the whole period of 18 days. CSFV pathology in kidney and skin resembles that of SLE. Furthermore, enzymes involved in the degradation of 1,25-dihydroxyvitamin D3 and of tryptophan to kynurenines were expressed at different levels in chronically diseased and recovered pigs. Both of these chemical processes may affect the functions of T helper/regulatory cells that are crucial for tempering the inflammatory response after a viral infection.
    Recent developments in basophil research : do basophils initiate and perpetuate type 2 T-helper cell responses?
    Beek, A.A. van; Knol, E.F. ; Vos, P. de; Smelt, M.J. ; Savelkoul, H.F.J. ; Neerven, R.J.J. van - \ 2013
    International Archives of Allergy and Immunology 160 (2013)1. - ISSN 1018-2438 - p. 7 - 17.
    thymic stromal lymphopoietin - antigen-presenting cells - chronic allergic inflammation - human blood basophils - in-vivo - cytokine production - dendritic cells - mast-cells - helminth infection - histamine-release
    Basophils account for only 0.1–1% of all peripheral blood leukocytes. They were considered to be a redundant cell type for a long time. However, several findings show a non-redundant role for basophils in type 2 T-helper cell (Th2) immune responses in helminth infections, allergy and autoimmunity. Both immunoglobulin-E-dependent and -independent pathways have been described to contribute to basophil activation. In addition, several recent studies reported that basophils can function as antigen-presenting cells and are important in the initiation of Th2 immune responses. However, there are also conflicting studies that do not corroborate the importance of basophils in Th2 immune responses. This review discusses the role of basophils in Th2 immune responses in view of these recent findings
    Inflammatory Chemokines Direct and Restrict Leukocyte Migration within Live Tissues as Glycan-Bound Gradients
    Sarris, M. ; Masson, J.B. ; Maurin, D. ; Aa, L.M. van der; Boudinot, P. ; Lortat-Jacob, H. ; Herbomel, P. - \ 2012
    Current Biology 22 (2012)24. - ISSN 0960-9822 - p. 2375 - 2382.
    cd8(+) t-cells - heparan-sulfate - neutrophil migration - dendritic cells - in-vivo - zebrafish - chemotaxis - motility - trafficking - attraction
    Chemokines are essential in many cell migration processes, including the recruitment of leukocytes to sites of infection [1-3]. In the latter context, chemokines promote leukocyte extravasation into the relevant tissue through a well-studied cascade of events [4-9]. It is widely believed that chemokines further guide leukocytes within tissues via chemotaxis, the directed migration along gradients of soluble ligands. However, the basic mechanism of chemokine action within tissues has yet to be formally addressed in vivo. We identified a chemokine (zCxcl8) that recruits zebrafish neutrophils to infection loci and analyzed its function directly within interstitial tissues of living larvae. Using noninvasive imaging and a controlled cellular source of zCxcl8, we found that zCxcl8 guides neutrophils in a 2-fold manner: by biasing cell speed according to direction (orthotaxis) and by restricting cell motility near the source. We further show that zCxcl8 establishes tissue-bound gradients in vivo by binding to heparan sulfate proteoglycans (HSPGs). Inhibition of this interaction compromised both directional guidance and restriction of neutrophil motility. Thus, by interacting with extracellular HSPGs, chemokines establish robust surface-bound (haptotactic) gradients that mediate both recruitment and retention of leukocytes at sites of infection.
    Breeding for high specific immune reactivity affects sensitivity to the environment
    Parmentier, H.K. ; Verhofstad, L.P.M. ; Vries Reilingh, G. de; Nieuwland, M.G.B. - \ 2012
    Poultry Science 91 (2012)12. - ISSN 0032-5791 - p. 3044 - 3051.
    red-blood-cells - secondary antibody-responses - intratracheal lipopolysaccharide - bacterial-endotoxin - molecular-patterns - dendritic cells - chickens - poultry - responsiveness - interleukin-1
    Lipopolysaccharides (LPS) are present in high levels in the air of chicken houses and likely have immune-modulating effects. In this study, layers from the 30th generation of a divergent selection experiment for humoral immune reactivity to subcutaneously administered sheep red blood cells were concurrently intratracheally challenged with human serum albumin (HuSA) and LPS at 7 and 12 wk of age following a crossing over design. Chickens selected for high humoral immune reactivity (H line) showed higher specific antibody responses to intratracheally administered HuSA and a higher level of natural antibody binding keyhole limpet hemocyanin compared with chickens genetically selected for low humoral immune reactivity (L line), and were also more sensitive to immune modulation by LPS at 7 wk of age. Body weight gain was negatively affected by LPS at 7 wk of age in the L line, but after 12 wk of age in the H line. Egg production was lower and delayed in the H line. We conclude that these chicken selection lines differ in sensitivity to the environment (LPS), and consequently may therefore also react differently to infection, vaccinations, and other immune responses. In addition, selection for immune responsiveness affected growth and egg lay
    L. plantarum, L. salivarius, and L. lactis Attenuate Th2 Responses and Increase Treg Frequencies in Healthy Mice in a Strain Dependent Manner
    Smelt, M.J. ; Haan, B.J. de; Bron, P.A. ; Swam, I. van; Meijerink, M. ; Wells, J. ; Faas, M.M. ; Vos, P. de - \ 2012
    PLoS ONE 7 (2012)10. - ISSN 1932-6203
    inflammatory-bowel-disease - lactobacillus-casei shirota - influenza-virus infection - placebo-controlled trial - complete genome sequence - blood mononuclear-cells - dendritic cells - double-blind - immune-system - acid bacteria
    Many studies on probiotics are aimed at restoring immune homeostasis in patients to prevent disease recurrence or reduce immune-mediated pathology. Of equal interest is the use of probiotics in sub-clinical situations, which are characterized by reduced immune function or low-grade inflammation, with an increased risk of infection or disease as a consequence. Most mechanistic studies focus on the use of probiotics in experimental disease models, which may not be informative for these sub-clinical conditions. To gain better understanding of the effects in the healthy situation, we investigated the immunomodulatory effects of two Lactobacillus probiotic strains, i.e. L. plantarum WCFS1 and L. salivarius UCC118, and a non-probiotic lactococcus strain, i.e. L. lactis MG1363, in healthy mice. We studied the effect of these bacteria on the systemic adaptive immune system after 5 days of administration. Only L. plantarum induced an increase in regulatory CD103+ DC and regulatory T cell frequencies in the spleen. However, all three bacterial strains, including L. lactis, reduced specific splenic T helper cell cytokine responses after ex vivo restimulation. The effect on IFN-¿, IL5, IL10, and IL17 production by CD4+ and CD8+ T cells was dependent on the strain administered. A shared observation was that all three bacterial strains reduced T helper 2 cell frequencies. We demonstrate that systemic immunomodulation is not only observed after treatment with probiotic organisms, but also after treatment with non-probiotic bacteria. Our data demonstrate that in healthy mice, lactobacilli can balance T cell immunity in favor of a more regulatory status, via both regulatory T cell dependent and independent mechanisms in a strain dependent manner.
    Characterization of epitope-tagged foot-and-mouth disease virus
    Seago, J. ; Jackson, T. ; Doel, C. ; Fry, E. ; Stuart, D. ; Harmsen, M.M. ; Charleston, B. ; Juleff, N. - \ 2012
    Journal of General Virology 93 (2012)11. - ISSN 0022-1317 - p. 2371 - 2381.
    classical swine-fever - g-h loop - differentiating infection - 3-dimensional structure - antigenic sites - dendritic cells - in-vivo - vaccines - vaccination - receptor
    Foot-and-mouth disease (FMD) is a highly contagious and economically devastating disease of cloven-hoofed animals with an almost-worldwide distribution. Conventional FMD vaccines consisting of chemically inactivated viruses have aided in the eradication of FMD from Europe and remain the main tool for control in endemic countries. Although significant steps have been made to improve the quality of vaccines, such as improved methods of antigen concentration and purification, manufacturing processes are technically demanding and expensive. Consequently, there is large variation in the quality of vaccines distributed in FMD-endemic countries compared with those manufactured for emergency use in FMD-free countries. Here, we have used reverse genetics to introduce haemagglutinin (HA) and FLAG tags into the foot-and-mouth disease virus (FMDV) capsid. HA- and FLAG-tagged FMDVs were infectious, with a plaque morphology similar to the non-tagged parental infectious copy virus and the field virus. The tagged viruses utilized integrin-mediated cell entry and retained the tag epitopes over serial passages. In addition, infectious HA- and FLAG-tagged FMDVs were readily purified from small-scale cultures using commercial antibodies. Tagged FMDV offers a feasible alternative to the current methods of vaccine concentration and purification, a potential to develop FMD vaccine conjugates and a unique tool for FMDV research.
    Role of heat-stable enterotoxins in the induction of early immune responses in piglets after infection with enterotoxigenic Escherichia coli
    Loos, M. ; Geens, M. ; Schauvliege, S. ; Gasthuys, F. ; Meulen, J. van der; Dubreuil, J.D. ; Goddeeris, B.M. ; Niewold, T.A. ; Cox, E. - \ 2012
    PLoS ONE 7 (2012)7. - ISSN 1932-6203
    toll-like-receptor - pancreatitis-associated protein - intestinal epithelial-cells - postweaning diarrhea - labile enterotoxin - gene-expression - dendritic cells - cytokine expression - human monocytes - net absorption
    Enterotoxigenic Escherichia coli (ETEC) strains that produce heat-stable (ST) and/or heat-labile (LT) enterotoxins are cause of post-weaning diarrhea in piglets. However, the relative importance of the different enterotoxins in host immune responses against ETEC infection has been poorly defined. In the present study, several isogenic mutant strains of an O149:F4ac(+), LT(+) STa(+) STb(+) ETEC strain were constructed that lack the expression of LT in combination with one or both types of ST enterotoxins (STa and/or STb). The small intestinal segment perfusion (SISP) technique and microarray analysis were used to study host early immune responses induced by these mutant strains 4 h after infection in comparison to the wild type strain and a PBS control. Simultaneously, net fluid absorption of pig small intestinal mucosa was measured 4 h after infection, allowing us to correlate enterotoxin secretion with gene regulation. Microarray analysis showed on the one hand a non-toxin related general antibacterial response comprising genes such as PAP, MMP1 and IL8. On the other hand, results suggest a dominant role for STb in small intestinal secretion early after post-weaning infection, as well as in the induced innate immune response through differential regulation of immune mediators like interleukin 1 and interleukin 17.
    B-glucans are involved in immune-modulation of THP-1
    Chanput, W. ; Reitsma, M. ; Kleinjans, L. ; Mes, J.J. ; Savelkoul, H.F.J. ; Wichers, H.J. - \ 2012
    Molecular Nutrition & Food Research 56 (2012)5. - ISSN 1613-4125 - p. 822 - 833.
    lactic-acid bacteria - factor-kappa-b - cell-line - cytokine production - interferon-gamma - dendritic cells - receptor - lentinan - mice - lipopolysaccharide
    Scope We aimed to examine different immunological aspects of ß-glucans derived from different food sources (oat, barley and shiitake) on phorbol myristate acetate (PMA)-differentiated THP-1 macrophages. Commercially purified barley ß-glucan (commercial BG) and lentinan were included to compare ß-glucans from the same origin but different degree of purity and processing. Methods and results Chemical composition and molecular weight distribution of ß-glucan samples were determined. Inflammation-related gene expression kinetics (IL-1ß, IL-8, nuclear factor kappa B [NF-¿B] and IL-10) after 3, 6 and 24 h of stimulation with 100 µg/mL ß-glucan were investigated. All tested ß-glucans mildly upregulated the observed inflammation-related genes with differential gene expression patterns. Similar gene expression kinetics, but different fold induction values, was found for the crude ß-glucan extracts and their corresponding commercial forms. Pre-incubation of THP-1 macrophages with ß-glucans prior to lipopolysaccharide (LPS) exposure decreased the induction of inflammation-related genes compared to LPS treatment. No production of nitric oxide (NO) and hydrogen peroxide (H2O2) was detected in ß-glucan stimulated THP-1 macrophages. Phagocytic activity was not different after stimulation by ß-glucan samples. Conclusion Based on these in vitro analyses, it can be concluded that the analysed ß-glucans have varying levels of immunomodulating properties, which are likely related to structure, molecular weight and compositional characteristic of ß-glucan
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